Osmotic Pressure-Controlled Gastrointestinal Delivery System

Osmotic Pressure-Controlled Gastrointestinal Delivery System These are systems fabricated by encapsulating an osmotic drug core containing an osmotically active drug (or a combination of an osmotically inactive drug with an osmotically active salt e.g. NACL) within a semi permeable membrane made from biocompatible polymer, e.g. cellulose acetate. Figure: Osmotic pressure-controlled drug delivery system (Elementary Osmotic Pump)

Osmotic Pressure-Controlled Gastrointestinal Delivery System A delivery orifice with a controlled diameter is drilled, using a laser beam, through the coating membrane for controlling the release of drug solutes. The polymer membrane should be: Semipermeable in nature. (permeable to influx the water from GIT into drug core but it is impermeable to drug solute). Rigid. Capable of maintaining the structural integrity of this system during the course of drug release.

Mechanism of releasing the drug from this system Water is continuously absorbed into the drug reservoir compartment through the semipermeable membrane to dissolve the osmotically active drug and/or salts. A gradient of osmotic pressure is thus created, under which the drug solutes are continuously pumped out over a prolonged period of time through the delivery of orifice at a rate defined by the following relationship:

Factor that affect zero order drug release The Permeability of water The effective surface area of membrane Is the osmotic pressure of the saturated soln of osmotically active drug and/or osmotic agent Is the osmotic pressure of GI fluid The solubility of the drug The thickness of the semipermeable membrane

Membrane Thickness Effect of coating membrane thickness on the rate and duration of zero-order release of indomethacin from osmotic pressure-controlled gastrointestinal delivery system

Drug Solubility APIs for osmotic delivery should have water solubility in the desired range (50-300 mg/ml) to optimize drug release. However, by modulating the solubility of these drugs within the core, effective release patterns may be obtained for the drugs, which might otherwise appear to be poor candidate for osmotic delivery. The following can be adopted for poorly soluble drugs 1. Use of swellable polymers: vinyl acetate copolymer, polyethylene oxide have uniform swelling rate which swells and pushes the drug as finely divided suspension. 2. Cyclodextrin complexation 3. Salt formation

Osmotic Pressure The simplest and most predictable way to achieve a constant osmotic pressure is to maintain a saturated solution of osmotic agent in the compartment. The following table shows osmotic pressure of commonly used solutes in CR formulations. When the osmotic pressure inside is much greater than that outside (GIT environment, the osmotic pressure, Δπ, becomes equal to π inside and the release rate is independent of the osmotic pressure of the GIT.

Effect of osmotic pressure in the osmotic pressure-controlled gastrointestinal delivery system on the rate of release of phenylpropanolamine

Size of delivery orifice As the size of orifice delivery increases, To achieve an optimal zero order delivery profile, the cross sectional area of the orifice must be smaller than a maximum size to minimize drug delivery by diffusion through the orifice. Furthermore, the area must be sufficiently large, above a minimum size to minimize hydrostatic pressure build up in the system. Large hydrostatic pressure can lead to deformation of the device resulting in unpredictable drug delivery. Amin ≤ Ao ≤ Amax The typical orifice size in osmotic pumps ranges from 600μm to 1 mm.

pH Because the semi permeable membrane is not permeable to ions (ions cannot readily exchange across it). The release rate of the drug from the system is independent of the pH of surrounding environment.

Comparison of the plasma profiles of phenylpropanolamine (PPA) in human delivered from Various dosage forms: (tri angle) PPA in solution formulation, (circle) PPA in dexatrim sustained release capsule and (dark circle) PPA in Acutrim tablets (osmotic pump)

Delay in onset of action: Lag time due to the need of hydration and build of the osmotic pressure Comparison of the time course for the amount of indomethacin delivered to humans using Various dosage forms. Indomethacin capsules: (0) 3 units taken at time 0 and (triangle) 1 unit each taken at time 0,4 and 8 hrs. Indomethacin-Osmotic pump (dark square) 1 unit of system A(7mg/hr) taken at time 0, And (white square) 1 unit of system B (9mg/hr) taken at time

Comparison of the efficiency of clinical Improvement In night pain, weight-bearing pain, and functional Activity in patients during treatment with indomethacin Delivered by osmotic pressure-controlled Osmosin tablets (with delivery rate of 7mg/hr) or by conventional capsule Formulation (25mg dose) Comparison of the extent of gastrointestinal Side effects experienced by osteoarthritis and Rheumatoid arthritis patients during treatment With indomethacin delivered by osmotic Pressure-controlled Osmosin tablets (with delivery rate Of 7mg/hr), conventional capsule formulation (25mg dose), Or placebo formulation.

Incorporation of Immediate release loading dose This is accomplished by dividing a therapeutic dose into two fractions. One-third of the therapeutic dose is designated as the “immediate-release” fraction and the remaining two thirds as the “controlled-released” fraction. The controlled-release fraction is encapsulated inside the semipermeable membrane coating; the immediate-release fraction is used to coat the external surface of the semipermeable membrane (figure) to provide the initial dose upon oral administration.

Dissolution studies indicated that, following the rapid release of the immediate-release dose, the PPA dose in the controlled-release core in the Acutrim tablet (osmotic pump) is delivered continuously in a controlled manner for a prolonged duration; the PPA dose from the dexatrim tablet (conventional sustained release) is released with only a slight prolongation in the drug release profile.

Push Pull Osmotic Pump Second generation of an osmotic pressure-controlled drug delivery system having a drug Reservoir compartment and an osmotically active compartment separated by a movable partition The osmotic pressure-controlled gastrointestinal delivery system can be further modified to constitute two compartments separated by a movable partition. The osmotically active compartment absorbs water from the gastrointestinal fluid to create an osmotic pressure that acts on the partition and forces it to move upward and to reduce the volume of the drug reservoir compartment and to release the drug formulation through the delivery orifice.

Controlled porosity osmotic pump Controlled porosity osmotic pump contains water-soluble additives in the coating membrane, which in contact with aqueous environment dissolves and results in formation of micro porous membrane. The resulting membrane is substantially permeable to both water and dissolved drug. The drug release from this type of system is independent of pH and follows zero order kinetics. The crystals of a water-soluble drug are compressed with excipients into a core tablet, which is coated with a non-GI-erodible polymer, e.g. vinyl chloride-vinyl acetate copolymer or polyvinyl acetate. The coating contains a small amount of a water-soluble pore-forming inorganic agent, e.g. Mg lauryl sulfate, Hydroxypropylcelluose or water soluble placticizer (glycerin) which creates pores when the tablet comes into contact with GI fluids.

Hydroxypropyl cellulose (HPC) polyvinyl acetate membrane (PVA) coating The porosity of the coating polymer can be varied by controlling the loading level of the water soluble additive, to give a slow or fast release at constant rates. Hydroxypropyl cellulose (HPC) polyvinyl acetate membrane (PVA) coating

Intragstric Osmotically controlled DDS This system consists of mainly two different part attached with each other, one is floating part and other is osmotic controlled part Floating part made-up of deformable polymeric bag containing liquid that gasify at body temperature. Osmotic pressure controlling part consists of two part, drug reservoir & osmotically active compartment.